Increased metabolism of glucose, via the sorbitol pathway, results in a redox imbalance similar to that caused by hypoxia (i.e., art increased cytosolic ratio of free NADHINAD+). This redox imbalance appears to result largely from increased oxidation of sorbitol to fructose, which is coupled to reduction of NAD+ to NADH by sorbitol dehydrogenase. It is independent of, and additive to. the same redox imbalance caused by hypoxia (which results from impaired oxidation of NADH to NAD+). This increased ratio of NADH/NAD+: I. Impacts directly or indirectly on the activity of several enzymes linked to the pathogenesis of diabetic complications. 2. Favors superoxide production. Many lines of evidence support the likelihood that increased oxidative stress, associated with this redox imbalance, plays an important role in the pathogenesis of diabetic complications.